CN102786467A - N-substitutional aryl pyridine ketone compound as well as preparation method and application of N-substitutional aryl pyridine ketone compound - Google Patents
N-substitutional aryl pyridine ketone compound as well as preparation method and application of N-substitutional aryl pyridine ketone compound Download PDFInfo
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- CN102786467A CN102786467A CN2012102896132A CN201210289613A CN102786467A CN 102786467 A CN102786467 A CN 102786467A CN 2012102896132 A CN2012102896132 A CN 2012102896132A CN 201210289613 A CN201210289613 A CN 201210289613A CN 102786467 A CN102786467 A CN 102786467A
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- China
- Prior art keywords
- pyridin
- phenyl
- methyl
- trifluoromethyl
- compound
- Prior art date
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- -1 aryl pyridine ketone compound Chemical class 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims 3
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims abstract description 12
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 8
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 9
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 6
- 125000000217 alkyl group Chemical group 0.000 claims 6
- 125000006725 C1-C10 alkenyl group Chemical group 0.000 claims 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims 4
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims 3
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 3
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 2
- 239000003054 catalyst Substances 0.000 claims 2
- 125000001188 haloalkyl group Chemical group 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 2
- ZRQBGAIYKFLVIM-UHFFFAOYSA-N 1-[4-[2-(diethylamino)ethoxy]phenyl]-5-methylpyridin-2-one Chemical compound C1=CC(OCCN(CC)CC)=CC=C1N1C(=O)C=CC(C)=C1 ZRQBGAIYKFLVIM-UHFFFAOYSA-N 0.000 claims 1
- OSDDMNFFPUMPCL-UHFFFAOYSA-N 1-[4-[2-(dimethylamino)ethoxy]phenyl]-5-methylpyridin-2-one Chemical compound C1=CC(OCCN(C)C)=CC=C1N1C(=O)C=CC(C)=C1 OSDDMNFFPUMPCL-UHFFFAOYSA-N 0.000 claims 1
- WPRGGWLRBBQEJW-UHFFFAOYSA-N 1-[4-[3-(diethylamino)propoxy]phenyl]-5-methylpyridin-2-one Chemical compound C1=CC(OCCCN(CC)CC)=CC=C1N1C(=O)C=CC(C)=C1 WPRGGWLRBBQEJW-UHFFFAOYSA-N 0.000 claims 1
- JDZMYZLMLRGWKP-UHFFFAOYSA-N 1-[4-[3-(dimethylamino)propoxy]phenyl]-5-methylpyridin-2-one Chemical compound C1=CC(OCCCN(C)C)=CC=C1N1C(=O)C=CC(C)=C1 JDZMYZLMLRGWKP-UHFFFAOYSA-N 0.000 claims 1
- ALYZXPUGHIHFAJ-UHFFFAOYSA-N 1-[4-[4-(diethylamino)butoxy]phenyl]-5-methylpyridin-2-one Chemical compound C1=CC(OCCCCN(CC)CC)=CC=C1N1C(=O)C=CC(C)=C1 ALYZXPUGHIHFAJ-UHFFFAOYSA-N 0.000 claims 1
- XYXHJAOOHKLPLV-UHFFFAOYSA-N 1-[4-[4-(dimethylamino)butoxy]phenyl]-5-methylpyridin-2-one Chemical compound C1=CC(OCCCCN(C)C)=CC=C1N1C(=O)C=CC(C)=C1 XYXHJAOOHKLPLV-UHFFFAOYSA-N 0.000 claims 1
- XIRVOZQUEOEKBG-UHFFFAOYSA-N 1-[4-[5-(diethylamino)pentoxy]phenyl]-5-methylpyridin-2-one Chemical compound C1=CC(OCCCCCN(CC)CC)=CC=C1N1C(=O)C=CC(C)=C1 XIRVOZQUEOEKBG-UHFFFAOYSA-N 0.000 claims 1
- GCMLJVDLEHSUJG-UHFFFAOYSA-N 1-[4-[5-(dimethylamino)pentoxy]phenyl]-5-methylpyridin-2-one Chemical compound C1=CC(OCCCCCN(C)C)=CC=C1N1C(=O)C=CC(C)=C1 GCMLJVDLEHSUJG-UHFFFAOYSA-N 0.000 claims 1
- GEAVSCDNWLQDOY-UHFFFAOYSA-N 5-methyl-1-[4-(2-morpholin-4-ylethoxy)phenyl]pyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C(C=C1)=CC=C1OCCN1CCOCC1 GEAVSCDNWLQDOY-UHFFFAOYSA-N 0.000 claims 1
- RDCAWPHUGOUZLP-UHFFFAOYSA-N 5-methyl-1-[4-(2-piperidin-1-ylethoxy)phenyl]pyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C(C=C1)=CC=C1OCCN1CCCCC1 RDCAWPHUGOUZLP-UHFFFAOYSA-N 0.000 claims 1
- LPRHUSLQCRNFJY-UHFFFAOYSA-N 5-methyl-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]pyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C(C=C1)=CC=C1OCCN1CCCC1 LPRHUSLQCRNFJY-UHFFFAOYSA-N 0.000 claims 1
- BIYFYPPSYAJOST-UHFFFAOYSA-N 5-methyl-1-[4-(3-morpholin-4-ylpropoxy)phenyl]pyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C(C=C1)=CC=C1OCCCN1CCOCC1 BIYFYPPSYAJOST-UHFFFAOYSA-N 0.000 claims 1
- MNQRLBOUFMWQFR-UHFFFAOYSA-N 5-methyl-1-[4-(3-piperidin-1-ylpropoxy)phenyl]pyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C(C=C1)=CC=C1OCCCN1CCCCC1 MNQRLBOUFMWQFR-UHFFFAOYSA-N 0.000 claims 1
- KLBMXMPSVPFBSN-UHFFFAOYSA-N 5-methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]pyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C(C=C1)=CC=C1OCCCN1CCCC1 KLBMXMPSVPFBSN-UHFFFAOYSA-N 0.000 claims 1
- JGLMJUBZZJLWHI-UHFFFAOYSA-N 5-methyl-1-[4-(4-morpholin-4-ylbutoxy)phenyl]pyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C(C=C1)=CC=C1OCCCCN1CCOCC1 JGLMJUBZZJLWHI-UHFFFAOYSA-N 0.000 claims 1
- QUJUKURTZCTMTR-UHFFFAOYSA-N 5-methyl-1-[4-(4-piperidin-1-ylbutoxy)phenyl]pyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C(C=C1)=CC=C1OCCCCN1CCCCC1 QUJUKURTZCTMTR-UHFFFAOYSA-N 0.000 claims 1
- MXAMYVGGEJTHAL-UHFFFAOYSA-N 5-methyl-1-[4-(4-pyrrolidin-1-ylbutoxy)phenyl]pyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C(C=C1)=CC=C1OCCCCN1CCCC1 MXAMYVGGEJTHAL-UHFFFAOYSA-N 0.000 claims 1
- GDMYJQRSWZOLTN-UHFFFAOYSA-N 5-methyl-1-[4-(5-morpholin-4-ylpentoxy)phenyl]pyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C(C=C1)=CC=C1OCCCCCN1CCOCC1 GDMYJQRSWZOLTN-UHFFFAOYSA-N 0.000 claims 1
- IGUMOCVJRAENHQ-UHFFFAOYSA-N 5-methyl-1-[4-(5-piperidin-1-ylpentoxy)phenyl]pyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C(C=C1)=CC=C1OCCCCCN1CCCCC1 IGUMOCVJRAENHQ-UHFFFAOYSA-N 0.000 claims 1
- JZYFHVIRUQBFIJ-UHFFFAOYSA-N 5-methyl-1-[4-(5-pyrrolidin-1-ylpentoxy)phenyl]pyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C(C=C1)=CC=C1OCCCCCN1CCCC1 JZYFHVIRUQBFIJ-UHFFFAOYSA-N 0.000 claims 1
- RHOHGVJIDXPMPK-UHFFFAOYSA-N 5-methyl-1-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]pyridin-2-one Chemical compound C1CN(C)CCN1CCOC1=CC=C(N2C(C=CC(C)=C2)=O)C=C1 RHOHGVJIDXPMPK-UHFFFAOYSA-N 0.000 claims 1
- DQJOVPLZQVITDJ-UHFFFAOYSA-N 5-methyl-1-[4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl]pyridin-2-one Chemical compound C1CN(C)CCN1CCCOC1=CC=C(N2C(C=CC(C)=C2)=O)C=C1 DQJOVPLZQVITDJ-UHFFFAOYSA-N 0.000 claims 1
- RGFJNBWDNOPWSJ-UHFFFAOYSA-N 5-methyl-1-[4-[4-(4-methylpiperazin-1-yl)butoxy]phenyl]pyridin-2-one Chemical compound C1CN(C)CCN1CCCCOC1=CC=C(N2C(C=CC(C)=C2)=O)C=C1 RGFJNBWDNOPWSJ-UHFFFAOYSA-N 0.000 claims 1
- MFFBFMHHTRJUBY-UHFFFAOYSA-N 5-methyl-1-[4-[5-(4-methylpiperazin-1-yl)pentoxy]phenyl]pyridin-2-one Chemical compound C1CN(C)CCN1CCCCCOC1=CC=C(N2C(C=CC(C)=C2)=O)C=C1 MFFBFMHHTRJUBY-UHFFFAOYSA-N 0.000 claims 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 1
- HNUALPPJLMYHDK-UHFFFAOYSA-N C[CH]C Chemical compound C[CH]C HNUALPPJLMYHDK-UHFFFAOYSA-N 0.000 claims 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 241000009298 Trigla lyra Species 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 239000011698 potassium fluoride Substances 0.000 claims 1
- 235000003270 potassium fluoride Nutrition 0.000 claims 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims 1
- 229940095064 tartrate Drugs 0.000 claims 1
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical class NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 25
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 abstract description 23
- 229960003073 pirfenidone Drugs 0.000 abstract description 21
- 208000005069 pulmonary fibrosis Diseases 0.000 abstract description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract description 4
- 230000002300 anti-fibrosis Effects 0.000 abstract description 3
- 150000002611 lead compounds Chemical class 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 17
- 239000007787 solid Substances 0.000 description 14
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- KAHVZNKZQFSBFW-UHFFFAOYSA-N n-methyl-n-trimethylsilylmethanamine Chemical compound CN(C)[Si](C)(C)C KAHVZNKZQFSBFW-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
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- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 3
- 208000029523 Interstitial Lung disease Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
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- 239000005457 ice water Substances 0.000 description 3
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- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 150000003233 pyrroles Chemical class 0.000 description 3
- NIDSRGCVYOEDFW-UHFFFAOYSA-N 1-bromo-4-chlorobutane Chemical compound ClCCCCBr NIDSRGCVYOEDFW-UHFFFAOYSA-N 0.000 description 2
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- 241000282414 Homo sapiens Species 0.000 description 2
- JOOMLFKONHCLCJ-UHFFFAOYSA-N N-(trimethylsilyl)diethylamine Chemical compound CCN(CC)[Si](C)(C)C JOOMLFKONHCLCJ-UHFFFAOYSA-N 0.000 description 2
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- 150000001721 carbon Chemical group 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 208000002440 photoallergic dermatitis Diseases 0.000 description 2
- 150000003217 pyrazoles Chemical class 0.000 description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BFCJNNBGPNOXMX-UHFFFAOYSA-N C1(=CC=CC=C1)N1C(C=CC=C1)=O.CC=1C=C(C=C(C(=O)O)C1)C(=O)O Chemical group C1(=CC=CC=C1)N1C(C=CC=C1)=O.CC=1C=C(C=C(C(=O)O)C1)C(=O)O BFCJNNBGPNOXMX-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
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Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种具有如式I所示结构的N-取代芳基吡啶酮化合物及其药学上可接受的盐。本发明还公开了一种所述N-取代芳基吡啶酮化合物的制备方法，以抗纤维化药物吡非尼酮为先导化合物，在保留吡啶酮母核基础上，在N-取代芳基的4位上引入不同的胺亚甲基醚结构得到一系列的N-(4-胺亚甲基醚)芳基吡啶酮。该方法具有原材料来源广泛、易于制备、方法操作简单、条件温和、易于控制、成本低、适于工业化生产等优点。本发明还公开了所述的N-取代芳基吡啶酮化合物及其药学上可接受的盐在治疗特发性肺纤维化疾病方面的应用，该类新化合物对人胚肺成纤维细胞具有较强的抑制作用，具有较好的抗肺纤维化应用前景。 The invention discloses an N-substituted aryl pyridone compound with the structure shown in formula I and a pharmaceutically acceptable salt thereof. The invention also discloses a preparation method of the N-substituted aryl pyridone compound. The anti-fibrosis drug pirfenidone is used as the lead compound, and on the basis of retaining the pyridone core, the N-substituted aryl A series of N-(4-amine methylene ether) aryl pyridones were obtained by introducing different amine methylene ether structures at the 4-position. The method has the advantages of wide source of raw materials, easy preparation, simple method operation, mild conditions, easy control, low cost, suitable for industrial production and the like. The present invention also discloses the application of the N-substituted aryl pyridone compound and its pharmaceutically acceptable salt in the treatment of idiopathic pulmonary fibrosis. It has a strong inhibitory effect and has a good application prospect in anti-pulmonary fibrosis. 
Description
Technical field
The present invention relates to a kind of verivate of pyridone, be specifically related to a kind of N-substituted aryl pyridinone compounds, pharmacy acceptable salt and preparation method and application.
Background technology
Fibrotic disease is one type of serious harm human life and healthy important diseases, like pulmonary fibrosis, renal fibrosis, hepatic fibrosis, myocardial fibrosis etc.Along with global industriallization and people live, the change of diet style, the sickness rate of fibrotic disease significantly increases.
Idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis; IPF); Claim cryptogenic fibrosing alveolitis (cryptogenic fibrosing alveolitis again; CFA), for agnogenio, be confined to lung, be the fiber voltinism interstitial lung disease of the chronic progressive external development of pathological characters with the coventional type interstitial pneumonia.IPF invades alveolus wall, alveolar space and then can develop into diffuse interstitial pulmonary fibrosis, finally can cause breathing decay and death.Relevant statistics shows that the intermediate value survival time of idiopathic pulmonary fibrosis patient after disease is examined out be 2-5 only, and 5 annual survival rates have only 20%.This disease prognosis mala still lacks the efficacious therapy method at present, belongs to one of listed difficult disease of WHO.
Along with development of social industrialization, IPF has the trend of obvious rising in recent years, and this area presses for exploitation effectively new compound and the medicine of treatment IPF.The medicine that can be used for fibrotic disease treatment at present seldom so far, has found that pyridine compounds is one type of effective fibrosis compound, and wherein, pirfenidone is a representative compound wherein.
Pirfenidone (Pirfenidone) is a kind of fibrosis new drug, for IPF provides new treat-ment.Pirfenidone is the micromolecular compound of finding the seventies in 20th century, and its chemical name is 5-methyl isophthalic acid-phenyl-2 (1H)-pyridone.The initial pirfenidone of discovering has certain anti-inflammatory, analgesic activity.Afterwards, the investigator finds that pirfenidone has restraining effect for the fibrosis of multiple tissues such as the heart, lung, kidney, liver, and increasing experimental result has confirmed the significant curative effect of pirfenidone aspect fibrosis.Pirfenidone is is at first researched and developed by U.S. Marnac company, after give American I nterMune company with global development power permission.In December, 2008, pirfenidone tablets (trade(brand)name Pirespa) authorizes the wild adopted company of Japanese salt at first to go on the market in Japan by InterMune company.In October, 2010, the imitated pirfenidone tablets (trade(brand)name Pirfenex) of selling of India Cipla company.In March, 2011, EU Committee has ratified the pirfenidone tablets (trade(brand)name Esbriet) of InterMune company exploitation, is used for the mild to moderate IPF patient of treatment adult.Pirfenidone is first idiopathic pulmonary fibrosis medicine of getting permission clinical application so far in European Union.
But pirfenidone has more spinoff clinically as a kind of oral medicine, comprises gastrointestinal upset (like vomiting, maldigestion, diarrhoea, apocleisis), weak and photoallergic dermatitis etc.Research shows: above these spinoffs are relevant with the high dosage of pirfenidone.Pharmacokinetic is found its plasma half-life short (healthy volunteer is oral, plasma half-life 2-2.5h).In order to keep effective plasma concns in the pirfenidone body, high dosage has just become essential treatment scheme with the high frequency medication.Present stage, people can only be through reducing dosage or stopping to treat the spinoff that alleviates pirfenidone.
Therefore, be necessary pirfenidone is further optimized, the pulmonary fibrosis resistant medicine of novel high-efficiency low-toxicity is provided.
Summary of the invention
In prior art; Many spinoffs such as the gastrointestinal upset that idiopathic pulmonary fibrosis disease therapeuticing medicine high dosage causes, weak and photoallergic dermatitis, the present invention provide a kind of pulmonary fibrosis resistant compound N-substituted aryl pyridone and pharmacy acceptable salt thereof of efficient, low toxicity.
A kind of N-substituted aryl pyridinone compounds has suc as formula structure shown in the I:
Wherein, R
1, R
2Be independently selected from H, C
1-C
10Alkyl, C
1-C
10Thiazolinyl, C
1-C
10Haloalkyl, cyanic acid, halogen or hydroxyl; R
3Be selected from H, C
1-C
10Alkyl, C
1-C
10Thiazolinyl or amino; X
1, X
2, X
4And X
5Be independently selected from H, halogen, C
1-C
10Alkyl, C
1-C
10Alkoxyl group, hydroxyl or sulfydryl; X
3Be Y (CH
2)
nR
4, wherein Y is O or S, n is 1-10; Described R
4Be open chain or cyclic tertiary amine structure NR
5R
6, R wherein
5, R
6Be independently selected from the straight or branched alkane that contains 1-3 carbon atom, or R
5, R
6With R
4In N constitute five yuan, hexa-atomic or seven-membered ring, described five yuan, hexa-atomic or seven-membered ring are oxazole, pyrroles, imidazoles, pyrazoles, piperidines, piperazine, N-METHYL PIPERAZINE, morpholine or high piperidines.
Compound with structure shown in the formula I has good in-vitro to suppress proliferation function to HELF HFL-I, has significant fibrosis effect.
As preferably, described R
1Be H, F, Cl, cyanic acid or hydroxyl; R
2Be methyl, ethyl, sec.-propyl, trifluoromethyl, difluoromethyl, vinyl or cyanic acid; R
3Be H, vinyl or amino; X
1, X
2, X
4And X
5Be independently selected from H, halogen, hydroxyl or sulfydryl; X
3Be Y (CH
2)
nR
4, wherein Y is O or S, n is 1-6; Described R
4Be open chain or cyclic tertiary amine structure NR
5R
6, R wherein
5, R
6Be independently selected from methyl, ethyl, propyl group, sec.-propyl, or R
5, R
6With R
4In N constitute pyrroles, imidazoles, piperidines, N-METHYL PIPERAZINE, morpholine or high piperidines.
Further preferred, described N-substituted aryl pyridinone compounds is selected from:
1-[4-(2-dimethylin-oxyethyl group)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(2-diethylin-oxyethyl group) phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
1-[4-(2-U-4527-1-base-oxyethyl group)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[2-(4-methyl-piperazine-1-yl)-oxyethyl group]-phenyl }-1H-pyridin-2-ones,
1-[4-(3-dimethylin-propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(3-diethylin-propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(3-tetramethyleneimine-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(3-piperidines-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[3-(4-methyl-piperazine-1-yl)-propoxy-]-phenyl }-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(3-morpholine-4-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
1-[4-(4-dimethylin-butoxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(4-diethylin-butoxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(4-tetramethyleneimine-1-base-butoxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(4-piperidines-1-base-butoxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[4-(4-methyl-piperazine-1-yl)-butoxy]-phenyl }-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(4-morpholine-4-base-butoxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(5-dimethylin-pentyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(5-diethylin-pentyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(5-tetramethyleneimine-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(5-piperidines-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[5-(4-methyl-piperazine-1-yl)-pentyloxy]-phenyl }-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(5-morpholine-4-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(6-dimethylin-hexyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(6-diethylin-hexyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(6-tetramethyleneimine-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(6-piperidines-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[6-(4-methyl-piperazine-1-yl)-hexyloxy]-phenyl }-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(6-morpholine-4-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(2-dimethylin-oxyethyl group)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(2-diethylin-oxyethyl group) phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[2-(4-methyl-piperazine-1-yl)-oxyethyl group]-phenyl }-1H-pyridin-2-ones,
1-[4-(3-dimethylin-propoxy-)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(3-diethylin-propoxy-)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(3-tetramethyleneimine-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(3-piperidines-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[3-(4-methyl-piperazine-1-yl)-propoxy-]-phenyl }-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(3-morpholine-4-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
1-[4-(4-dimethylin-butoxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(4-diethylin-butoxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(4-tetramethyleneimine-1-base-butoxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(4-piperidines-1-base-butoxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[4-(4-methyl-piperazine-1-yl)-butoxy]-phenyl }-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(4-morpholine-4-base-butoxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(5-dimethylin-pentyloxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(5-diethylin-pentyloxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(5-tetramethyleneimine-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(5-piperidines-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[5-(4-methyl-piperazine-1-yl)-pentyloxy]-phenyl }-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(5-morpholine-4-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(6-dimethylin-hexyloxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(6-diethylin-hexyloxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(6-tetramethyleneimine-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(6-piperidines-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[6-(4-methyl-piperazine-1-yl)-hexyloxy]-phenyl }-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(6-morpholine-4-base-hexyloxy)-phenyl]-1H-pyridin-2-ones.
The present invention also provides a kind of preparation method of described N-substituted aryl pyridinone compounds, has the starting material wide material sources, advantages such as cost is low, method is simple to operate, mild condition.
A kind of preparation method of N-substituted aryl pyridinone compounds; With the pyriphenanthrenone as anti-fibrosis medicine is lead compound; Keeping on the pyridone parent nucleus basis; Through on 4 of N-substituted aryl, introducing the methylene ether structure, further obtain a series of N-(4-amine methylene ether) aryl pyridinones again with the secondary amine reaction with the nucleophilic substitution reaction of halohydrocarbon.Specifically comprise the steps:
(1) will suc as formula the compound of II with as the compound of formula III in organic solvent, acid binding agent exists to react down and obtains the compound suc as formula IV, temperature of reaction is room temperature～backflow, 6～12 hours reaction times;
(2) suc as formula the compound of IV with suc as formula the secondary amine of V in organic solvent, catalyzer exists down with acid binding agent, reacts to obtain the target compound suc as formula I, temperature of reaction is room temperature～70 ℃, 3～14 days reaction times;
Wherein, R
1, R
2Be independently selected from H, C
1-C
10Alkyl, C
1-C
10Thiazolinyl, C
1-C
10Haloalkyl, cyanic acid, halogen or hydroxyl; R
3Be selected from H, C
1-C
10Alkyl, C
1-C
10Thiazolinyl or amino; X
1, X
2, X
4And X
5Be independently selected from H, halogen, C
1-C
10Alkyl, C
1-C
10Alkoxyl group, hydroxyl or sulfydryl; Described R
4Be open chain or cyclic tertiary amine structure NR
5R
6, R wherein
5, R
6Be independently selected from the straight or branched alkane that contains 1-3 carbon atom, or R
5, R
6With R
4In N constitute five yuan, hexa-atomic or seven-membered ring, described five yuan, hexa-atomic or seven-membered ring are oxazole, pyrroles, imidazoles, pyrazoles, piperidines, piperazine, N-METHYL PIPERAZINE, morpholine or high piperidines, n is 1-10, Y is O or S.
Compound III, V are the commercial goods, and compound I I can be that 200810201706.9 Chinese invention patent disclosed method makes according to application number.
Organic solvent in the said step (1) is acetone, butanone or ethanol; Acid binding agent is salt of wormwood, yellow soda ash or Potassium monofluoride.
As preferably, the organic solvent in the said step (1) is an acetone; Acid binding agent is a salt of wormwood.
Organic solvent in the said step (2) is acetone or N, dinethylformamide; Acid binding agent is salt of wormwood or yellow soda ash; Catalyzer is potassiumiodide, Soiodin.
As preferably, the solvent in the said step (2) is N, dinethylformamide; Acid binding agent is a salt of wormwood; Catalyzer is a Soiodin.
The various N-substituted aryl pyridinone compounds that reaction is made are dissolved in a kind of in ether, acetone, methyl alcohol, ethanol, the ETHYLE ACETATE, and dropping inorganic acid or organic acid solution are processed pharmacy acceptable salt.
Specifically be that various N-substituted aryl pyridinone compounds are dissolved in a kind of in ether, acetone, methyl alcohol, ethanol or the ETHYLE ACETATE, the dripping hydrochloric acid ethyl acetate solution is processed hydrochloride under ice-water bath; Or various N-substituted aryl pyridinone compounds are dissolved in a kind of in ether, acetone, methyl alcohol, ethanol or the ETHYLE ACETATE, drip and wait a mole methylsulfonic acid, its mesylate; Or various N-substituted aryl pyridinone compounds are dissolved in a kind of in ether, acetone, methyl alcohol, ethanol or the ETHYLE ACETATE, drip concentrated sulfuric acid solution down in ice-water bath and process vitriol, or the like.
The invention also discloses the application in preparation treatment idiopathic pulmonary fibrosis disease medicament of described N-substituted aryl pyridinone compounds and pharmacy acceptable salt thereof.Preliminary pharmacological testing finds that these compounds great majority have good in-vitro to suppress proliferation function to HELF HFL-I, suppress proliferation function and are better than pirfenidone greatly.
The present invention is to be lead compound with the pyriphenanthrenone as anti-fibrosis medicine, is keeping on the pyridone parent nucleus basis, on 4 of N-substituted aryl, introduces different amine methylene ether structures and obtains a series of N-(4-amine methylene ether) aryl pyridinones.Have the starting material wide material sources, be easy to preparation, simple to operate, the mild condition of method, cost is low, is suitable for advantages such as suitability for industrialized production.
Embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
Embodiment 1,1-(4-hydroxyl-phenyl)-5-methyl isophthalic acid H-pyridin-2-ones (IIa): according to application number is that 200810201706.9 Chinese invention patent disclosed method makes.m.p.167-169℃。
1HNMR(δ，CDCl
3)：7.34-7.37(m，1H)，7.14(s，1H)，6.97-7.00(d，2H)，6.68(s，1H)，6.62-6.66(m，2H)，2.12(s，3H)。
Embodiment 2,1-[4-(3-chlorine propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (IVb):
Compound I Ia 5.4g (26.9mmol), salt of wormwood 7.3g (53.8mmol) are placed the 250mL three-necked bottle, add acetone 200mL, refluxing and stirring 30min; Add 1-bromo-3-chloro-propane (IIIb) 6mL (60.8mmol), back flow reaction 8 hours is filtered; Filter cake is with washing with acetone 3 times; Merge diafiltration liquid, be concentrated into part, add the sherwood oil crystallization and spend the night.Filter, washing, drying gets incarnadine solid IVb, yield 93%.m.p.107-108℃。
1HNMR(δ，CDCl
3)：7.08-7.29(m，4H)，6.99(d，2H)，6.60(d，1H)，4.14(t，2H)，3.75(t，2H)，2.25(m，2H)，2.09(s，3H)。
Embodiment 3,1-[4-(4-chlorine butoxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (IVc):
Operating process replaces 1-bromo-3-chloro-propane (IIIb) referring to embodiment 2 with 1-bromo-4-chloro-butane (IIIc).Obtain light yellow cured article IVc, yield 97%.m.p.57-58℃。
1HNMR(δ，CDCl
3)：7.11-7.30(m，4H)，6.99(d，2H)，6.62(d，1H)，4.04(t，2H)，3.64(t，2H)，2.11(s，3H)，1.99(m，4H)。
Embodiment 4,1-[4-(2-chloroethoxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (IVa):
Operating process replaces 1-bromo-3-chloro-propane (IIIb) referring to embodiment 2 with 1-bromo-2-chloro-ethane (IIIa).Obtain light yellow cured article IVa, yield 82%.m.p.118-120℃。
1HNMR(δ，CDCl
3)：7.10-7.31(m，4H)，6.99-7.02(d，2H)，6.59-6.62(d，1H)，4.27(t，2H)，3.84(t，2H)，2.11(s，3H)。
Embodiment 5,1-[4-(2-chlorine pentyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (IVd):
Operating process replaces 1-bromo-3-chloro-propane (IIIb) referring to embodiment 2 with 1-bromo-5-chloro-pentane (IIId).Obtain white solid IVd, yield 54%.m.p.87-88℃。
1HNMR(δ，CDCl
3)：7.10-7.29(m，4H)，6.98(d，2H)，6.62(d，1H，)，4.01(t，2H)，3.59(t，2H)，2.10(s，3H)，1.62-1.89(m，6H)。
Embodiment 6,1-[4-(2-chlorine hexyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (IVe):
Operating process replaces 1-bromo-3-chloro-propane (IIIb) referring to embodiment 2 with 1-bromo-6-chloro-hexane (IIIe).Obtain white solid IVe, yield 90%.m.p.67-68℃。
1HNMR(δ，CDCl
3)：7.10-7.29(m，4H)，6.98(d，2H)，6.62(d，1H，)，4.00(t，2H)，3.57(t，2H)，2.10(s，3H)，1.52-1.84(m，10H)。
Embodiment 7,1-[4-(3-dimethylin-propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (1b)
With compound IV b 500mg (1.8mmol), N, TMSDMA N dimethylamine hydrochloride 323mg (3.96mmol), salt of wormwood 995mg (7.2mmol), sodium iodide 90mg (0.6mmol) place the 50mL three-necked bottle, add DMF (25mL) under the N2 atmosphere, 70 ℃ of reactions of oil bath 3 days.Be cooled to room temperature, add 50mL water, stir 30min, ethyl acetate extraction 3 times; Merge organic phase, wash 2 times, anhydrous sodium sulfate drying filters; Be concentrated into small volume,, obtain faint yellow solid powder 1b, yield 28% with eluent (ETHYLE ACETATE+0.3% triethylamine) column chromatography.m.p.46-47℃。
1HNMR(δ，CDCl
3)：7.08-7.27(m，4H)，6.96-6.98(d，2H)，6.58-6.60(d，1H)，4.04(t，2H)，2.45(t，2H)，2.56(s，6H)，2.09(s，3H)，1.97(m，2H)。
Embodiment 8,1-[4-(3-diethylin-propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (2b)
Operating process is used N referring to embodiment 7, and TMSDEA N diethylamine replaces N, TMSDMA N dimethylamine hydrochloride.Obtain yellow oil 2b, yield 51%.
1HNMR(δ，CDCl
3)：7.08-7.27(m，4H)，6.96-6.98(d，2H)，6.58-6.60(d，1H)，4.03(t，2H)，2.52-2.63(m，6H)，2.09(s，3H)，1.94(m，2H)，1.04(t，6H)。
Embodiment 9,5-methyl isophthalic acid-[4-(3-tetramethyleneimine-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones (3b)
Operating process replaces N referring to embodiment 7 with Pyrrolidine, the TMSDMA N dimethylamine hydrochloride.Obtain white solid 3b, yield 46%.m.p.125-126℃。
1HNMR(δ，CDCl
3)：7.08-7.26(m，4H)，6.96-6.98(d，2H)，6.58-6.60(d，1H)，4.05(t，2H，)，2.62(t，2H)，2.52(s，4H)，2.09(s，3H)，2.01(m，2H)，1.79(s，4H)。
Embodiment 10,5-methyl isophthalic acid-[4-(3-piperidines-1-base-propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (4b)
Operating process replaces N referring to embodiment 7 with piperidines, the TMSDMA N dimethylamine hydrochloride.Obtain white-yellowish solid 4b, yield 49%.m.p.97-98℃。
1HNMR(δ，CDCl
3)：7.08-7.26(m，4H)，6.96-6.98(d，2H)，6.57-6.60(d，1H)，4.02(t，2H)，2.48(t，2H)，2.41(s，4H)，2.08(s，3H)，1.97(m，2H)，1.59(m，4H)，1.44(d，2H)。
Embodiment 11,5-methyl isophthalic acid-{ 4-[3-(4-methyl-piperazine-1-yl)-propoxy-]-phenyl }-1H-pyridin-2-ones (5b)
Operating process replaces N, TMSDMA N dimethylamine hydrochloride referring to embodiment 7 with the 4-N-METHYL PIPERAZINE.Obtain white-yellowish solid 5b, yield 33%.m.p.94-95℃。
1HNMR(δ，CDCl
3)：7.08-7.28(m，4H)，6.96-6.98(d，2H)，6.58-6.60(d，1H)，4.04(t，2H)，2.51-2.55(m，10H)，2.30(s，3H)，2.09(s，3H)，1.98(m，2H)。
Embodiment 12,5-methyl isophthalic acid-[4-(3-morpholine-4-base-propoxy-)-phenyl-1 h-pyridin-2-ketone (6b)
Operating process is replaced N, TMSDMA N dimethylamine hydrochloride referring to embodiment 7 with morpholino.Obtain pale yellow solid 6b, yield 77%.m.p.87-88℃。
1HNMR(δ，CDCl
3)：7.08-7.28(m，4H)，6.96-6.98(d，2H)，6.58-6.60(d，2H)，4.05(t，2H)，3.72(t，4H)，2.52(t，2H)，2.47(s，4H)，2.09(s，3H)，1.98(m，2H)。
Embodiment 13,1-[4-(2-dimethylin-oxyethyl group)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (1a)
Operating process replaces compound IV b referring to embodiment 7 with compound IV a, obtains yellow solid 1a, yield 29%, m.p.90-92 ℃.
1HNMR(δ，CDCl
3)：7.09-7.28(m，4H)，6.97-6.99(d，2H)，6.58-6.61(d，1H)，4.10(t，2H)，2.75(t，2H)，2.35(s，6H)，2.09(s，3H)。
Embodiment 14,1-[4-(2-diethylin-oxyethyl group) phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (2a)
Operating process replaces compound IV b referring to embodiment 7 with compound IV a, uses N, and TMSDEA N diethylamine replaces N, and the TMSDMA N dimethylamine hydrochloride obtains yellow oil 2a, yield 19%.
1HNMR(δ，CDCl
3)：7.09-7.28(m，4H)，6.97-6.99(d，2H)，6.58-6.61(d，1H)，4.08(t，2H)，2.90(t，2H)，2.68(q，4H)，2.10(s，3H)，1.08(t，6H)。
Embodiment 15,5-methyl isophthalic acid-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones (3a)
Operating process replaces compound IV b referring to embodiment 7 with compound IV a, replaces N with Pyrrolidine, and the TMSDMA N dimethylamine hydrochloride obtains yellow solid 3a, yield 43%.m.p.106-108℃。
1HNMR(δ，CDCl
3)：7.07-7.26(m，4H)，6.96-6.98(d，2H)，6.56-6.58(d，1H)，4.12(t，2H)，2.86(t，2H)，2.59-2.63(m，4H)，2.07(s，3H)，1.18-1.78(m，4H)。
Embodiment 16,5-methyl isophthalic acid-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones (4a)
Operating process replaces compound IV b referring to embodiment 7 with compound IV a, replaces N with piperidines, the TMSDMA N dimethylamine hydrochloride.Obtain light yellow solid 4a, yield 74%.m.p.107-108℃。
1HNMR(δ，CDCl
3)：7.08-7.21(m，4H)，6.96-6.99(d，2H)，6.57-6.59(d，1H)，4.13(t，2H)，2.78(t，2H)，2.50(s，4H)，2.09(s，3H)，1.58-1.63(m，4H)，1.46(d，2H)。
Embodiment 17,1-[4-(2-U-4527-1-base-oxyethyl group)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (5a)
Operating process replaces compound IV b referring to embodiment 7 with compound IV a, replaces N with U-4527, the TMSDMA N dimethylamine hydrochloride.Obtain yellow oil 5a, yield 77%.
1HNMR(δ，CDCl
3)：7.09-7.21(m，4H)，6.96-6.99(d，2H)，6.58-6.60(d，1H)，4.09(t，2H)，2.95(t，2H)，2.79(t，4H)，2.09(s，3H)，1.60-1.66(m，8H)。
Embodiment 18,5-methyl isophthalic acid-[4-(2-morpholine-4-base-oxyethyl group)-phenyl-1 h-pyridin-2-ketone (6a)
Operating process replaces compound IV b referring to embodiment 7 with compound IV a, replaces N, TMSDMA N dimethylamine hydrochloride with morpholino.Obtain pale yellow crystals 6a, yield 15%.m.p.118-119℃。
1HNMR(δ，CDCl
3)：7.08-7.28(m，4H)，6.97-6.99(d，2H，6-H)，6.58-6.60(d，1H)，4.14(t，2H)，3.73-3.75(m，4H)，2.82(t，2H)，2.58(s，4H)，2.09(s，3H)。
Embodiment 19,5-methyl isophthalic acid-[4-(5-piperidines-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones (4d)
Operating process replaces compound IV b referring to embodiment 7 with compound IV d, replaces N with piperidines, the TMSDMA N dimethylamine hydrochloride.Obtain white solid 4d, yield 91%.m.p.92-93℃。
1HNMR(δ，CDCl
3)：7.08-7.26(m，4H)，6.93-6.96(d，2H)，6.57-6.59(d，1H)，3.97(t，2H)，2.29-2.37(m，6H)，2.08(s，3H)，1.81(m，2H)，1.43-1.59(m，10H)。
Embodiment 20,5-methyl isophthalic acid-[4-(6-piperidines-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones (4e)
Operating process replaces compound IV b referring to embodiment 7 with compound IV e, replaces N with piperidines, the TMSDMA N dimethylamine hydrochloride.Obtain white solid 4e, yield 64%.m.p.67-68℃。
1HNMR(δ，CDCl
3)：7.08-7.26(m，4H)，6.94-6.96(d，2H)，6.57-6.60(d，1H)，3.97(t，2H)，2.29-2.37(m，6H)，2.08(s，3H)，1.79(m，2H)，1.33-1.61(m，12H)。
The hydrochloride of embodiment 21, compound 4b
Get compound 4b 1.0g, be dissolved in 10mL ETHYLE ACETATE, be cooled to 0 ℃ in the ice-water bath, drip saturated HCl ethyl acetate solution, centrifugal, get white solid, yield 70%.
Embodiment 22, pulmonary fibrosis resistant biological activity test method:
HELF's isolated culture: choose HELF HFL-I, contain conventional cultivation of α-MEM substratum of 10%FBS.
Mtt assay is measured the vitro inhibition effect of N-substituted aryl pyridinone compounds to HELF HFL-I:
The cell strain in vegetative period of taking the logarithm, the adjustment concentration of cell suspension is 1 * 10
5/ mL, every hole 100 μ L cell suspension inoculations in 96 porocyte culture plates, the inoculation 24h after administration (100 μ L/ hole); Establish blank group, cell control group and 5 concentration respectively and tried drug group (1.67,3.33,5.00; 6.67,10.00 μ mol/mL), each concentration is established 3 multiple holes.After after the dosing 20 hours, every hole adds 100 μ LMTT (1mg/mL is with α-MEM nutrient solution dissolving); Cultivate 4h for 37 ℃; Discard and add 150 μ L acidifying Virahols (containing 0.04mol/L HCl) in each hole behind the liquid, lucifuge placement 30min, ELIASA mensuration 570nm place absorbancy; Calculating receives the proliferation inhibition rate of reagent thing to the HFL-I cell, and with
Software (GraphPad
TMSoftware Inc) computer program match inhibition curve calculation is tried the half-inhibition concentration (IC of thing to HELF HFL-I propagation (24h)
50).The gained result sees table 1:
Table 1 compound is to the IC of HELF HFL-I
50Value
From table 1, can find out: (1) most of new compounds have certain restraining effect to HELF HFL-I.(2) 9 new compound IC
50Less than the positive control pirfenidone.(3) 4b has higher cell proliferation inhibition rate, IC
50Value is little 8 times than pirfenidone.(4) generally speaking, such new compound has pulmonary fibrosis resistant application prospect preferably, thereby has good commercial value.
Need not further to set forth in detail, believe and adopt the disclosed content in front, those skilled in the art can use the present invention to greatest extent.Therefore, the embodiment of front is interpreted as only illustrating, but not limits scope of the present invention by any way.
Claims (10)
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| RU2738844C2 (en) * | 2016-04-14 | 2020-12-17 | Гуанчжоу Джойо Фарматек Ко., Лтд | Containing a substitute, which is butane, in the heterocyclic ring a pyridone derivative for treating fibrosis and inflammatory diseases |
| CN109311859B (en) * | 2016-04-14 | 2022-01-21 | 广州嘉越医药科技有限公司 | Heteroatom cyclobutane substituent containing pyridone derivatives for the treatment of fibrotic and inflammatory diseases |
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| CN113476448A (en) * | 2021-07-09 | 2021-10-08 | 中南大学 | Application of meflonizone in preparation of medicine for treating acute lung injury |
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